This invention relates to novel isothiazole derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene that upon activation leads to the formation of malignant tumor cells). Many oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype. It has been shown that certain tyrosine kinases may be mutated or overexpressed in many human cancers such as brain, melanoma, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid cancers. Furthermore, the overexpression of a ligand for a tyrosine kinase receptor may result in an increase in the activation state of the receptor, resulting in proliferation of the tumor cells or endothelial cells. Thus, it is believed that inhibitors of receptor tyrosine kinases, such as the compounds of the present invention, are useful as selective inhibitors of the growth of mammalian cancer cells.
It is known that growth factors such as the neurotrophin family activate receptor tyrosine kinases such as trks. The neurotrophin family of growth factors includes nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5). These basic proteins are approximately 120 amino acids in length, share approximately 50% sequence homology, and are highly conserved among mammalian species (Issackson et al., FEBS Lett. 285:260–64, 1991). NGF was the first growth factor discovered and remains the best characterized neurotrophin. NGF is required for normal development of sensory and sympathetic neurons and for normal function of these cells in adult life (Levi-Montalcini, Annu. Rev. Neurosci. 5:341–362, 1982; Yankner et al., Annu. Rev. Biochem 51:845–868, 1982).
Neurotrophin binding and activation of a set of high affinity receptors (trks) is necessary and sufficient to mediate most of the biological effects of the neurotrophins. The trks are transmembrane proteins that contain an extracellular ligand binding domain, a transmembrane sequence, and a cytoplasmic tyrosine kinase domain. The trks comprise a family of structurally related proteins with preferential binding specificities for the individual neurotrophins. TrkA, which is sometimes referred to as trk, is a high-affinity receptor for NGF, but it can also mediate biological responses to NT-3 under particular conditions (Kaplan et al. Science 252:554–558, 1991; Klein et al., Cell 65, 189–197, 1991; Cordon-Cardo et al., Cell 66:173–183, 1991). TrkB binds and mediates functions of BDNF, NT-3, and NT4/5 (Klein et al. Cell 66:395–403, 1991; Squinto et al., Cell 65:885–893, 1991; Klein et al. Neuron 8:947–956, 1992). TrkC is relatively specific for NT-3 (Lamballe et al., Cell 66:967–979, 1991).
The Trk family of receptor tyrosine kinases is frequently expressed in lung, breast, pancreatic and prostate cancers. See, Endocrinol. 141: 118, 2000; Cancer Res., 59: 2395, 1999; Clin. Cancer Res. 5: 2205, 1999; and Oncogene 19: 3032, 2000. The tyrosine kinase activity of Trk is believed to promote the unregulated activation of cell proliferation machinery. Recent pre-clinical data suggests that Trk inhibitors suppress the growth of breast, pancreatic and prostate tumor xenografts. Furthermore, it is believed that Trk inhibition may be tolerated in cancer patients. It is also believed by those in the art that inhibitors of either TrkA or TrkB kinases have utility against some of the most common cancers, such as brain, melanoma, squamous cell, bladder, gastric, pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung, renal, kidney, ovarian, gynecological, and thyroid cancer. It is further believed that additional therapeutic uses of Trk inhibitors include pain, neuropathy and obesity.
Isothiazole derivatives are known and have identified as herbicides in U.S. Pat. Nos. 4,059,433 and 4,057,416, both assigned to FMC Corporation. Isothiazoles derivatives useful for prolferative disease are referred to in U.S. Pat. No. 6,235,764, assigned to Pfizer, Inc.